This proposal is a branch out pilot study that is closely related to the K08 project. The primary goal of the K08 project is to study the mechanisms of antiviral cytokines. During this study, we have gained significant insights into the interferon signaling mechanisms in liver cells, which prompts us to propose this pilot project to study the interactions of the Hepatitis C viral (HCV) proteins and interferon signaling molecules, and their role in interferon resistance. The current proposal will significantly contribute to the overall goal of the K08. The R03 support will allow me to gain additional resources to successfully achieve the career development goal: being a fully independent investigator. HCV infection is a major chronic liver disease that is a rapidly increasing public health problem. Without an effective vaccine being available, the current treatment is combination therapy with interferon (IFN) and Ribavirin, which is only partially effective. Despite substantial research, the underlying molecular mechanisms for interferon resistance are not fully understood. The outcome of IFN-based treatment is undoubtedly related to the interaction of the virus and the host. Several studies have demonstrated that viral proteins can modulate cellular response to IFN, which may be a potential mechanism of IFN resistance. However, little is known about the mechanisms of such interactions. This proposal will focus on the mechanisms of host cellular factor-viral protein interactions in HCV interferon resistance. Our hypothesis is that the negative regulators of the JAK-STAT pathway may play a critical role in HCV interferon resistance, and the HCV core protein may have an impact on the expression of these regulators. This hypothesis will be tested by two specific aims: 1. To determine the role of SOCS3 in IFN resistance and to define the mechanisms by which SOCS3 regulates STAT activation; 2. To determine the mechanisms by which HCV core protein regulates SOCS3 expression. These two specific aims will allow us to gain insights into the interactions between the cell signaling molecules and viral proteins and their role in IFN response in liver cells. The conclusions of our proposed study will permit us to launch further experimentation aimed at improving IFN treatment efficacy and circumventing IFN resistance.